Arnaud Vincent

Incorporating functional MR imaging into diffusion tensor tractography in the preoperative assessment of the corticospinal tract in patients with brain tumors

BACKGROUND AND PURPOSE: Our goal was to improve the preoperative assessment of the corticospinal tract (CST) in patients with brain tumors. We investigated whether the integration of functional MR imaging (fMRI) data and diffusion tensor (DT) tractography can be used to evaluate the spatial relationship between the hand and foot fibers of the CST and tumor borders. MATERIALS AND METHODS: We imaged 10 subjects: 1 healthy volunteer and 9 patients. Imaging consisted of a 3D T1-weighted sequence, a gradient-echo echo-planar imaging (EPI) sequence for fMRI, and a diffusion-weighted EPI sequence for DT tractography. DT tractography was initiated from a seed region of interest in the white matter area subjacent to the maximal fMRI activity in the precentral cortex. The target region of interest was placed in the cerebral peduncle. RESULTS: In the healthy volunteer, we successfully tracked hand, foot, and lip fibers bilaterally by using fMRI-based DT tractography. In all patients, we could track the hand fibers of the CST bilaterally. In 4 patients who also performed foot tapping, we could clearly distinguish hand and foot fibers. We were able to depict the displacement of hand and foot fibers by tumor and the course of fibers through areas of altered signal intensity. CONCLUSION: Incorporating fMRI into DT tractography in the preoperative assessment of patients with brain tumors may provide additional information on the course of important white matter tracts and their relationship to the tumor. Only this approach allows a distinction between the CST components, while visualization of the CST is improved when fiber tracking is hampered by tumor (infiltration) or perifocal edema.

Gene therapy of experimental malignant mesothelioma using adenovirus vectors encoding the HSVtk gene

Replication-defective adenovirus vectors were generated in which the gene of interest (lacZ, luciferase or HSV-tk) is driven by the adenovirus major late promoter (MLP) or the human cytomegalovirus immediate–early gene promoter/enhancer (CMV). In vitro experiments with rat (II-45) and human (MERO 25) mesothelioma cell lines revealed that the CMV promoter was stronger than the MLP promoter regarding levels of expression of the luciferase reporter gene and ganciclovir (GCV) killing efficiency after tk gene transfer. Following administration of IG.Ad.CMV.lacZ recombinant adenovirus (Introgene, IG) into the pleural cavity of Fischer rats with established mesothelioma, a widespread distribution of infectious virus particles through the thorax contents was demonstrated. However, a relatively small proportion of tumor cells were transduced. Nevertheless, a strong tumor growth inhibition was observed following treatment with IG.Ad.CMV.TK recombinant adenovirus and GCV. Separate groups of rats inoculated on day 0 with 105 II-45 cells into the pleural cavity, received 7 × 109 infectious particles of IG.Ad. CMV.TK on day 1, day 2, day 4 or day 8. One day after virus administration, 25 mg/kg GCV or PBS (controls) was injected i.p. (intraperitoneally) twice daily. On day 15, all animals were killed. Significant tumor regression, equivalent to 5 log cell kill, occurred in the treated rats suggesting an impressive bystander effect. In a survival study, animals were treated 9 days after inoculation of 105 tumor cells with IG.Ad.CMV.TK and a 14 days course of GCV. This treatment prolonged symptom-free survival time from 19 days in the controls to 33 days in the treated group. These responses can be best explained by assuming continued tk expression in or around the tumor tissue during GCV treatment. Our results confirm and extend earlier findings with the same model and demonstrate the potential of the herpes simplex virus thymidine kinase suicide gene therapy as a local treatment for malignant mesothelioma.

Towards improving the safety and diagnostic yield of stereotactic biopsy in a single centre

BackgroundPreviously, we reported on our single centre results regarding the diagnostic yield of stereotactic needle biopsies of brain lesions. The yield then (1996–2006) was 89.4%. In the present study, we review and evaluate our experience with intraoperative frozen-section histopathologic diagnosis on-demand in order to improve the diagnostic yield.MethodsOne hundred sixty-four consecutive frameless biopsy procedures in 160 patients (group 1, 2006–2010) were compared with the historic control group (group 2, n = 164 frameless biopsy procedures). Diagnostic yield, as well as demographics, morbidity and mortality, was compared. Statistical analysis was performed by Students t, Mann–Whitney U, Chi-square test and backward logistic regression when appropriate.ResultsDemographics were comparable. In group 1, a non-diagnostic tissue specimen was obtained in 1.8%, compared to 11.0% in group 2 (p = 0.001). Also, both the operating time and the number of biopsies needed were decreased significantly. Procedure-related mortality decreased from 3.7% to 0.6% (p = 0.121). Multivariate analysis only proved operating time (odds ratio (OR), 1.012; 95% confidence interval (CI), 1.000–1.025; p = 0.043), a right-sided lesion (OR, 3.183; 95% CI, 1.217–8.322; p = 0.018) and on-demand intraoperative histology (OR, 0.175; 95% CI, 0.050–0.618; p = 0.007) important factors predicting non-diagnostic biopsies.ConclusionsThe importance of a reliable pathological diagnosis as obtained by biopsy must not be underestimated. We believe that when performing stereotactic biopsy for intracranial lesions, next to minimising morbidity, one should strive for as high a positive yield as possible. In the present single centre retrospective series, we have shown that using a standardised procedure and careful on-demand intraoperative frozen-section analysis can improve the diagnostic yield of stereotactic brain biopsy procedures as compared to a historical series.

Cognitive functioning early after surgery of gliomas in eloquent areas

OBJECT Patients with gliomas frequently have cognitive deficits, and surgery can exacerbate these deficits. Preoperative assessment is therefore crucial in patients undergoing surgery for glioma in eloquent areas, because the proximity of functional areas increases the risk of permanent postoperative cognitive disturbances. Although pre- and postoperative language and motor function in patients with glioma have been investigated frequently, data on good cognition studies are scarce. Most studies have focused on clinical neurological functioning or have only used brief neurological instruments. The authors investigated whether surgery for glioma in eloquent areas influences cognition early after surgery, by using an elaborate test protocol. METHODS Twenty-eight patients with gliomas of the left hemisphere in language and nonlanguage areas were assessed before and 3 months after surgery with a comprehensive neuropsychological test protocol. The authors performed a correlation analysis between change in cognitive performance and tumor characteristics (that is, location, volume, pathological features, and histological grade) and between cognitive change and treatment-related factors (the extent of the resection and postoperative treatment with chemo- and radiotherapy). RESULTS Both pre- and postoperatively, the mean performance of the patients was worse than the performance of the normal population in the language domain, the memory domain, and the executive functions (p < 0.05). Postoperatively, a decline was found in the language domain (t = 2.34, p = 0.027) and in the executive functions (t = 2.45, p = 0.022). However, cognitive change postsurgery was influenced by the location of the tumor; the decrease of cognitive score in the language domain was only observed in patients with tumors in or close to language areas (t = 2.33, p = 0.029). No effect on cognitive change was found for the other tumor characteristics and treatment-related factors. CONCLUSIONS This study underlines the importance of the use of a neuropsychological test protocol before and after surgery in patients with glioma, because several tasks in the domains of language, memory, and executive functions appeared to deteriorate after surgery. Tumor resection in language areas increases the risk of cognitive deficits in the language domain postoperatively.

Intracerebral injection of adenovirus harboring the HSVtk gene combined with ganciclovir administration: toxicity study in nonhuman primates

A high dose (1–2.5 × 1010 infectious units) of recombinant adenovirus harboring the herpes simplex thymidine kinase gene (IG.Ad.MLPI.TK) was injected into the white matter of the right frontal lobe in two rhesus monkeys (M. mulatta). Injection of the vector was followed by systemic ganciclovir administration (10 mg/kg per day) for 14 days. During treatment no clinical symptoms were observed. Histopathological analysis of the brain at day 18 showed a 5 mm necrotic area at the site of the virus injection. This area was invaded and surrounded by inflammatory cells and acti- vated astrocytes (gliosis). Immunohistochemical analysis of the infiltrates revealed the presence of predominantly mononuclear cells. In the vicinity of the lesion perivascular cuffs were seen containing T lymphocytes and clusters of B lymphocytes. From this preclinical study we conclude that the toxicity of adenotk/GCV is acceptable and treatment of patients with malignant gliomas using this kind of therapy is feasible. However, careful dose finding in clinical studies is recommended.

Exercise improves quality of life in patients with cancer: a systematic review and meta-analysis of randomised controlled trials

Purpose Exercise may be associated with increased health-related quality of life (QoL) in patients with cancer, but it is not prescribed as standard care during or after cancer treatment. We systematically reviewed the methodological quality of, and summarised the evidence from, randomised controlled trials (RCTs). A meta-analysis was performed to examine the effectiveness of exercise in improving the QoL in patients with cancer, during and after medical treatment. Methods RCTs that met the PICO (Patient Intervention Control Outcome) format were included in this study. 16 RCTs were identified through a search of Embase, Medline (OvidSP) and the Cochrane Library. These trials were reviewed for substantive results and the methodological quality was assessed using the Delphi criteria list. Results Exercise interventions differed widely in content, frequency, duration and intensity. Based on the meta-analysis, exercise improved QoL significantly in patients with cancer as compared to usual care (mean difference 5.55, 95% CI (3.19 to 7.90), p<0.001). Other outcomes closely related to QoL, such as fatigue and physical functioning, also improved. Conclusions Exercise has a direct positive impact on QoL in patients with cancer, during and following medical intervention. Exercise is a clinically relevant treatment and should be an adjunct to disease therapy in oncology.

Laser speckle imaging identification of increases in cortical microcirculatory blood flow induced by motor activity during awake craniotomy

OBJECT The goal of awake neurosurgery is to maximize resection of brain lesions with minimal injury to functional brain areas. Laser speckle imaging (LSI) is a noninvasive macroscopic technique with high spatial and temporal resolution used to monitor changes in capillary perfusion. In this study, the authors hypothesized that LSI can be useful as a noncontact method of functional brain mapping during awake craniotomy for tumor removal. Such a modality would be an advance in this type of neurosurgery since current practice involves the application of invasive intraoperative single-point electrocortical (electrode) stimulation and measurements. METHODS After opening the dura mater, patients were woken up, and LSI was set up to image the exposed brain area. Patients were instructed to follow a rest-activation-rest protocol in which activation consisted of the hand-clenching motor task. Subsequently, exposed brain areas were mapped for functional motor areas by using standard electrocortical stimulation (ECS). Changes in the LSI signal were analyzed offline and compared with the results of ECS. RESULTS In functional motor areas of the hand mapped with ECS, cortical blood flow measured using LSI significantly increased from 2052 ± 818 AU to 2471 ± 675 AU during hand clenching, whereas capillary blood flow did not change in the control regions (areas mapped using ECS with no functional activity). CONCLUSIONS The main finding of this study was that changes in laser speckle perfusion as a measure of cortical microvascular blood flow when performing a motor task with the hand relate well to the ECS map. The authors have shown the feasibility of using LSI for direct visualization of cortical microcirculatory blood flow changes during neurosurgery.

The impact of surgery in molecularly defined low-grade glioma: an integrated clinical, radiological, and molecular analysis

Background Extensive resections in low-grade glioma (LGG) are associated with improved overall survival (OS). However, World Health Organization (WHO) classification of gliomas has been completely revised and is now predominantly based on molecular criteria. This requires reevaluation of the impact of surgery in molecularly defined LGG subtypes. Methods We included 228 adults who underwent surgery since 2003 for a supratentorial LGG. Pre- and postoperative tumor volumes were assessed with semiautomatic software on T2-weighted images. Targeted next-generation sequencing was used to classify samples according to current WHO classification. Impact of postoperative volume on OS, corrected for molecular profile, was assessed using a Cox proportional hazards model. Results Median follow-up was 5.79 years. In 39 (17.1%) histopathologically classified gliomas, the subtype was revised after molecular analysis. Complete resection was achieved in 35 patients (15.4%), and in 54 patients (23.7%) only small residue (0.1-5.0 cm3) remained. In multivariable analysis, postoperative volume was associated with OS, with a hazard ratio of 1.01 (95% CI: 1.002-1.02; P = 0.016) per cm3 increase in volume. The impact of postoperative volume was particularly strong in isocitrate dehydrogenase (IDH) mutated astrocytoma patients, where even very small postoperative volumes (0.1-5.0 cm) already negatively affected OS. Conclusion Our data provide the necessary reevaluation of the impact of surgery in molecularly defined LGG and support maximal resection as first-line treatment for molecularly defined LGG. Importantly, in IDH mutated astrocytoma, even small postoperative volumes have negative impact on OS, which argues for a second-look operation in this subtype to remove minor residues if safely possible.

Dynamic aphasia following low-grade glioma surgery near the supplementary motor area: A selective spontaneous speech deficit

We describe a patient (KO) with reduced spontaneous speech, resembling dynamic aphasia, after awake glioma surgery in the proximity of the supplementary motor area. Naming, repetition, and comprehension were intact. He was tested with an extensive neuropsychological test-battery and a protocol for dynamic aphasia at 1 year. He presented with postoperative reduced spontaneous speech and selective executive function deficits. Most language recovery took place at 3 months postoperatively, whereas the executive functions improved between 3 months and 1 year. Results suggest that resection near the supplementary motor area could increase the risk of cognitive disturbances at long term, especially language.

Crossed Cerebrocerebellar Language Lateralization: An Additional Diagnostic Feature for Assessing Atypical Language Representation in Presurgical Functional MR Imaging

BACKGROUND AND PURPOSE: Determining language dominance with fMRI is challenging in patients with brain tumor, particularly in cases of suspected atypical language representation. Supratentorial activation patterns must be interpreted with great care when the tumor is in or near the presumed language areas, where tumor tissue or mass effect can lead to false-negative fMRI results. In this study, we assessed cerebrocerebellar language fMRI lateralization in healthy participants and in patients with brain tumors with a focus on atypical language representation. MATERIALS AND METHODS: Twenty healthy participants and 38 patients with a brain tumor underwent fMRI with a verb-generation task. Cerebral and cerebellar language lateralizations were separately classified as left-sided, right-sided, or symmetric. Electrocortical stimulation was performed in 19 patients. With the McNemar test, we evaluated the dependency between language lateralization in the cerebrum and cerebellum, and with Pearson correlation analysis, the relationship between the cerebral and cerebellar lateralization indices. RESULTS: There was a significant dependency between cerebral and cerebellar language activation, with moderate negative correlation (Pearson r = −0.69). Crossed cerebrocerebellar language activation was present in both healthy participants and patients, irrespective of handedness or typical or atypical language representation. There were no discordant findings between fMRI and electrocortical stimulation. CONCLUSIONS: Language lateralization in the cerebellum can be considered an additional diagnostic feature to determine language dominance in patients with brain tumor. This is particularly useful in cases of uncertainty, such as the interference of a brain tumor with cerebral language activation on fMRI and atypical language representation.